Human immunodeficiency virus (HIV) infects millions of humans annually and is a leading cause of death worldwide. In the absence of medical therapy, death usually results within 10 years of infection. The introduction of antiretroviral (ART) drugs has significantly diminished morbidity and mortality. However, ART must be taken throughout life, and the several long term effects (e.g. dyslipidemia, mitochondrial dysfunction, exocrine pathology) have only recently been appreciated. Studies that address the adverse effects of ART on the oral mucosa are lacking. Our goal is to elucidate the effects of ART on the function of oral soft tissues, focusing on epithelial cell biology. This knowledge is a requisite for understanding the long-term implications of ART on the critical importance of the mucosa and epithelium in controlling oral opportunistic infections in HIV infected individuals. The GENERAL HYPOTHESIS of the proposed research is select ART drugs dysregulate oral epithelial cell biology, impacting on normal proteasome pathways, epithelial cell homeostasis, and parameters of innate immunity, resulting in deleterious alternations of the oral mucosa and the epithelial cell's ability to respond to microbial pathogens. Our specific aims are to 1) examine the effect of ART on the proteasome-proteolytic pathway in oral epithelial cells, 2) determine the effects of ART on toll-like receptor (TLR) signaling pathways in oral epithelial cells, and 3) determine the effects of ART on oral epithelial cell differentiation. [unreadable] [unreadable] Specific biochemical and molecular methodologies are described that will allow us to systematically determine if ART adversely effects the proteasome function, TLR signaling and ability of epithelial cells to differentiate. These processes are key to maintaining oral mucosal health in patients who are infected with HIV and for understanding how opportunistic infections develop despite the presence of ART. [unreadable] [unreadable] [unreadable]